In an attempt to develop a more rational approach to the treatment of extremity melanoma, our group has focused on better defining melphalan pharmacokinetics and its relationship to toxicity and outcome, as well as by defining the drug resistance mechanisms prevalent in melanoma in transit lesions and then treating with known inhibitors of identified resistance pathways. In these ways we may be able to improve the efficacy of alkylating agents, allowing use of a lower drug dose, which could lead to diminished extremity toxicity. The alkylating agent melphalan is the primary agent used for HILP for treatment of extremity in transit melanoma. The extent of tumor reduction produced by this regimen is undoubtedly related to the drug sensitivity of the patient's tumor. It is uncertain whether tumor response is related to drug concentration alone or in addition to alkylating resistance mechanisms. In this study we propose 2 aims: 1) Define that tumor response is directly related to measured intratumor drug levels of melphalan and correlate the pharmacokinetics of melphalan with toxicities and therapeutic outcome in the animal limb perfusion model and human and 2) Define the mechanisms of alkylating agent resistance present in human tumor biopsies and a spectrum of human melanoma cell lines xenoplanted in the nude rat, and the effect of these mechanisms on tumor response. Define strategies to overcome/bypass the mechanism(s) of resistance identified.